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168 7 Histamine and antihistamines
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Fig. 7.39: Alternative theory for the binding of cimetidine to the agonist site.
Fig. 7.40: Nitropyrrole derivative of cimetidine.
Fig. 7.41: An isocytosine ring incorporated into a moiety present in cimetidine.
7.8.4 Desolvation
The guanidino and thiourea groups are polar and hydrophilic. This implies that they
are probably solvated (i.e., surrounded by a “water layer”). Before the hydrogen bond
is established, the water layer has to be removed. The more solvated the group is, the
more difficult the interaction with the receptor becomes. If desolvation is a factor
influencing biological activity, a reduction of the polar group s olvati on should increase activity. One way to achieve this would be to increase the hydrophobic character of the terminus group of the molecule.
7.8 Cimetidine development 169
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A study was carried out on a set of cimetidine analogs containing different flat
aminal systems [Z, an aminal or aminoacetal is a functional group that has two amino
groups attached to the same carbon atom: –C(NR
)(NR2)–; R may be hydrogen or an
2
alkyl group] in order to investigate whether there was any relationship between the
antagonistic activity and the hydrophobic character of the aminal groups (Fig. 7.42).
Fig. 7.42: Analogs of cimetidine with flat aminal systems (Z).
This study showed that antagonistic activity was proportional to the hydrophobicity of
the Z aminal unit and supported the theory of desolvation [eq. (7.1) and Fig. 7.43]:
log ð1=CÞ = 2.0 log π + 7.4(7:1)
An important finding is that the 2-nitroethene-1,1-diamine group behaves as an outlier
(Fig. 7.43). The reasoning for this will be considered next.
Fig. 7.43: The antagonist activity is proportional to the hydrophobicity (log π) of the Z-aminal moiety.
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7.8.5 Development of the 2-nitroethene-1,1-diamine group
It was decided to see what would happen if the polar imine nitrogen of cimetidine
was replaced b y a nonpolar carbon atom. This was expected to give rise to the 2nitroethene-1,1-diamine group. Unfortunately, 2-nitroethene-1,1-diamines are more
likely to exist as their amidine tautomers, unless a strong electronegative group (e.g.,
) is attached to the C atom (Fig. 7.44).
NO
2
Fig. 7.44: Tautomeric equilibrium.
The compound with the above moiety was more active than one might think. This indicates the presence of another variable influencing its biological activity and further
studies focused on the orientation of the dipole moment (Fig. 7.45).
Fig. 7.45: Dipole moments of several antagonistic groups.
In Fig. 7.45 the orientation of the dipole moment is defined by the φ angle between the
dipole moment and the N–R bond. Compounds with the cyanoguanidino, 2-nitroethene1,1-diamine, and nitropyrrole groups have a high antagonistic activity and have orientations of the dipole moments of 13°, 33°, and 27°, respectively. The isocitosine and imida-
7.8 Cimetidine development 171
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zolinone groups give rise to a lower activity and have orientations of 2° and −6°, respectively. The strength of the dipole moment (μ) does not seem to be crucial.
Adipole–dipole interaction takes place when the drug approaches the binding
site. The dipoles line up, orientating the drug, and a good interaction with the binding
site occurs if the binding groups are positioned correctly in relatio n to the binding
regions. This produces a good activity (Fig. 7.46).
Fig. 7.46: Orientation effects on the receptor active site.
This directs the drug in a specific way before the hydrogen bond takes place and determines the strength of the hydrogen bond to be established. If the dipole moment is
correctly oriented as in the 2-nitroethene-1,1-diamine analog, the group will be correctly positioned for a strong hydrogen bond and will lead to high activity (Fig. 7.46).
Fig. 7.47: Ideal and observed orientations of the dipole.
QSAR studies were performed to determine the φ optimal angle for the activity. This
gave an optimal angle of 30° (Fig. 7.47). A correlation was obtained between the orientation of the distribution coefficient and the activity [eq. (7.2)]:
log ð1=CÞ = 9.12 cos φ + 0.6 log π − 2.71 (7:2)
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The term cos φ shows that activity decreases if the orientation of φ separates from the
ideal value of 30°. With this ideal angle, φ is 0° and cos 0° = 1, whereby the biological
activity is maximal. The 2-nitroethene-1,1-diamine group did not give rise to a more
powerful cimetidine analog, but we will see it again in ranitidine.
7.9 Variation of the imidazole ring and the cyanoguanidine
moiety of cimetidine: ranitidine
Glaxo showed that the imidazole could be replaced by a furan with a substituent containing a nitrogen atom and thus molecule 7.1 was obtained (Fig. 7.48). Nevertheless,
its variable melting point and low crystallinity made its pharmaceutical development
difficult and the subsequent change of the cyanoguanidino group of 7.1 by the 2nitroethene-1,1-diamine group gave rise to ranitidine.
Fig. 7.48: Variation of the imidazole ring and the cyanoguanidine moiety of cimetidine to give ranitidine
®
(Zantac
Ranitidine has fewer side effects than cimetidine, lasts longer, and is 4–5 times more
active. The SAR results are as follows:
– The 2-nitroethene-1,1-diamine group is optimal for activity, but can be replaced
by other π-planar systems capable of forming hydrogen bonds.
– The activity would decrease if a sulfur atom was placed next to the ring.
– Replacing the furan with more hydrophobic rings, such as phenyl or thiophene,
reduces activity.
– Di-substitution at 2.5 is the best model for the furan ring.
– Substitution of a methyl group at C-3 of the furan ring eliminates the activity,
while the equivalent substitution in the imidazole series increases it.
These results imply that cimetidine and ranitidine do not interact in the same way
with the H
nitro ethylene di-amino group attached to cimetidine leads to a decrease in activity.
).
receptor. This assertion is supported by the finding that the corresponding
2
7.11 Comparison between H1 and H2 antagonists 173
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7.10 Summary of cimetidine design
The evolution in the development of cimetidine is summarized in Fig. 7.49. Note the
change in the tautomeric forms from burimamide to methiamide. The trade name of
Tagamet corresponds to the accumulation of uppercase letters of the phrase “anTAG-
onist And ciMETidine”.
Fig. 7.49: Evolution in the development of cimetidine.
7.11 Comparison between H1 and H2 antagonists
At the structural level, the differences between the two types of antagonists are quite
remarkable, as shown in Fig. 7.50.
H1 antihistamines are compounds with high lipophilicity due to terminal aryl
groups. This results in greater penetration into the CNS and central side effects. In
contrast, H2 antagonists are polar and hydrophilic molecules, largely due to the high
dipole moment of the substituents at the terminal side chain. These substituents pres-
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Fig. 7.50: Structural differences between H1 and H2 antagonists.
ent delocalized and low ionized systems at physiological pH, which explains their limited penetration into the CNS as well as the practical absence of effects at this level.
The work done by Black, Ganellin, and coworkers was a true example of careful
rational development, with thoughtful consideration of the chemical properties used
to identify the optimal compound. The development of cimetidine represents a breakthrough in pharmaceutical chemistry in using the physiological approach, which is
focused on the selection of a therapeutic target.
7.12 Fundamentals
H1 antihistamines: They are used as antiallergy agents
Phenbenzamine, dimenhydrinate, chlorpheniramine, promethazine, loratadine,
and desloratadine
H2 antihistamines → they are used as antiulcer drugs
Evolution in the development of cimetidine N
methiamide → cimetidine
Preferred tautomeric forms of histamine and burimamide
Introduction of the cyanoguanidine group in cimetidine
Bredereck reaction
Cimetidine synthesis
α
-guanylhistamine burimamide →
8 Enzymatic inhibitors I
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8.1 Goals
– Foster knowledge of the drugs that act at these levels
– Foster knowledge of the fundamental role of enzymatic inhibition in the design
of new drugs
– Make the reader aware of the existence of various peptides that play important
roles in life
– Introduce the student to modern antihypertensive drugs
8.2 Introduction
In general, enzymes are simpler pharmacological targets to study than receptors
since they are easier to purify and their active sites and their catalysis mechanisms
are relatively accessible. It is useful to distinguish between two possible situations
when it comes to using an enzyme as a target for drug action:
– First, they may be pharmacodynamic enzyme inhibitors, which act when the
causes or symptoms of a disease are due to an alteration of an enzymatic reaction
usually occurring in the healthy organism
– Second, there are enzymatic chemotherapeutic inhibitors, which act when a dis-
ease is caused by external agents, generally by bacteria, viruses, fungi, or parasites. These drugs can inhibit important enzymes for survival that are not found
in the host or, if present, can inhibit their function selectively. Chemotherapeutics
are also called antitumor agents that act by in hibiting enzymes for which there
are only quantitative differences between normal and tumor cells, whereby selective inhibition is practically impossible, at least in vitro
8.3 Carbonic anhydrase (CA) inhibitors
Carbonic anhydrase (CA) is an enzyme that catalyzes the formation of carbonic acid
from carbon dioxide and water (Fig. 8.1).
Fig. 8.1: Formation of carbonic acid.
https://doi.org/10.1515/9783111316888-008
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CA is located in the walls of the proximal kidney tubule cells and its net effect is the
reabsorption of sodium bicarbonate together with the osmotic equivalent of water
(Fig. 8.2).
Fig. 8.2: Mechanism of sodium bicarbonate reabsorption by CA.
It has been observed that diuretic effects of certain sulfonamides are associated with
their ability to competitively inhibit CA enzymes. This inhibitory action is most commonlyundertakenbyintheprimarysulfonamides, given their structural analogy
with carbonic acid, the natural substrate of the enzyme (Fig. 8.3). A similar interaction
with the active center of the enzyme for both types of compounds can be postulated.
On the other hand, it is essential that the primary sulfonamide be relatively acidic.
This is achieved by introducing electron-withdrawing aromatic systems, such as 1,3,4thiadiazole, present in various diuretic sulfonamides such as acetazolamide, the first
drug of this group (Fig. 8.4).
Fig. 8.3: Interaction of a primary sulfonamide and carbonic acid with the active center of CA.
8.3 Carbonic anhydrase (CA) inhibitors 177
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Fig. 8.4: Acetazolamide.
CA is also found in other tissues where its inhibition may lead to useful therapeutic
effects. Thus, since it participates in the formation of aqueous humor, CA inhibitors
(CAIs) will lead to a decrease in the reuptake of sodium bicarbonate and water from
the tear to the aqueous humor, which is useful in the treatment of glaucoma (Fig. 8.5).
Fig. 8.5: Decreased aqueous humor volume: utility in the treatment of glaucoma.
With the prolonged use of diuretic CAs, urine becomes more alkaline and blood becomes more acidic. When acidosis occurs, CAs lose efficacy as diuretics and remain
ineffective until the body’s acid-base balance is restored. For this reason, this class of
compounds has a limited utility as diuretics. Today, they are most commonly used in
the treatment of glaucoma, in which they inhibit CA in the eye, reduce the rate of
aqueous humor formation, and consequently reduce intraocular pressure.
Research in the field of diuretic sulfonamides has been very successful in recent
years. Through molecular modifications of CA inhibitors, diuretic sulfonamides that
are structurally related, but are governed by different mechanisms to those outlined
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